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Chromatin marks identify critical cell types for fine mapping complex trait variants

Abstract

If trait-associated variants alter regulatory regions, then they should fall within chromatin marks in relevant cell types. However, it is unclear which of the many marks are most useful in defining cell types associated with disease and fine mapping variants. We hypothesized that informative marks are phenotypically cell type specific; that is, SNPs associated with the same trait likely overlap marks in the same cell type. We examined 15 chromatin marks and found that those highlighting active gene regulation were phenotypically cell type specific. Trimethylation of histone H3 at lysine 4 (H3K4me3) was the most phenotypically cell type specific (P < 1 × 10−6), driven by colocalization of variants and marks rather than gene proximity (P < 0.001). H3K4me3 peaks overlapped with 37 SNPs for plasma low-density lipoprotein concentration in the liver (P < 7 × 10−5), 31 SNPs for rheumatoid arthritis within CD4+ regulatory T cells (P = 1 × 10−4), 67 SNPs for type 2 diabetes in pancreatic islet cells (P = 0.003) and the liver (P = 0.003), and 14 SNPs for neuropsychiatric disease in neuronal tissues (P = 0.007). We show how cell type–specific H3K4me3 peaks can inform the fine mapping of associated SNPs to identify causal variation.

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Figure 1: Overview of the statistical approach.
Figure 2: Evaluating the significance of phenotypic cell type specificity for different marks.
Figure 3: SNPs for four complex traits overlap H3K4me3 marks in specific cell types.
Figure 4: Cell type specificity for four sets of SNPs.
Figure 5: Selected phenotypically associated loci with high cell type specificity.

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Acknowledgements

We thank M. Daly, M. Kellis, D. Diogo, X. Hu, Y. Okada, R. Plenge, S. Ripke, G. Srivastava, E. Stahl and S. Sunyaev for critical feedback and discussion. G.T. is supported by the Rubicon grant from The Netherlands Organization for Scientific Research (NWO). B.E.S. and S.R. are supported by the Harvard University Milton Fund, and Brigham and Women's Hospital. S.R. is also supported by funds from the US NIH (K08AR055688 and U01HG0070033) and the Arthritis Foundation. X.S.L. is also supported by funds from the US NIH (R01 HG004069). We thank the ENCODE Project, supported by the NHGRI, and the NIH Roadmap Epigenomics Mapping Consortium for making data available.

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S.R. led the study. G.T., C.S., S.R., B.H. and H.X. performed the analysis. G.T., C.S., S.R., B.E.S. and X.S.L. wrote the manuscript. All authors reviewed the final manuscript.

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Correspondence to Soumya Raychaudhuri.

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Trynka, G., Sandor, C., Han, B. et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat Genet 45, 124–130 (2013). https://doi.org/10.1038/ng.2504

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